TODO:

Preambule

Load data

## 
## DETECTIVE_Ph2 DETECTIVE_Ph3        GATHER 
##           329           522           251
## TQ doses in data:
## 
## No Radical Cure            PQ15           TQ100           TQ300            TQ50 
##             186             265              56             482              55 
##           TQ600 
##              56
## [1] 482
## [1] 7.692307
## [1] 4.929577
## 27 patients were lost to follow-up before 1 month
## 39 patients were lost to follow-up before 4 months
## 125 patients were lost to follow-up before 6 months
## 
##   0   1 
## 775 298
## 
##   0   1 
## 713 360

Data summaries

Kaplan Meier time to recurrence

## [1] 186 170 379  56  44 265

## 
##    [0,0.01) [0.01,3.75) [3.75,6.25) [6.25,8.75)   [8.75,15]          PQ 
##         186         170         379          56          44         265
##              
##               [0,0.01) [0.01,3.75) [3.75,6.25) [6.25,8.75) [8.75,15]  PQ
##   Brazil            58          61         105           6         3  82
##   Cambodia          10           0          16           3         0   9
##   Colombia           0           0          13           0         0   6
##   Ethiopia          14           0          21           7         0  13
##   India             10          21           8           4         7   6
##   Peru              62          56         140          21        18  93
##   Philippines        1           0           3           0         0   2
##   Thailand          31          32          48          11        16  39
##   Vietnam            0           0          25           4         0  15
## Range of mg/kg weights:
## [1]  0.55 14.29
## Median number of methb measurements is 12 (range 2 to 19)
## 
##   0   1 
## 775 298
##              
##                 0   1
##   [0,0.01)     81 101
##   [0.01,3.75) 112  57
##   [3.75,6.25) 289  79
##   [6.25,8.75)  50   4
##   [8.75,15]    43   0
##   PQ          200  57
##     Dose (mg) Rec 4 mths (%)     n
## 1    [0,0.01)           55.5 182.0
## 2 [0.01,3.75)           33.7 169.0
## 3 [3.75,6.25)           21.5 368.0
## 4 [6.25,8.75)            7.4  54.0
## 5   [8.75,15]            0.0  43.0
## 6          PQ           22.2 257.0

CYP2D6

## 
## FALSE  TRUE 
##   716   384
##          
##             0 0.5   1 1.5   2
##   *1/*1     0   0   0   0 407
##   *1/*10    0   0   0  56   0
##   *1/*17    0   0   0  34   0
##   *1/*3     0   0   3   0   0
##   *1/*4     0   0  62   0   0
##   *1/*41    0   0   0  27   0
##   *1/*5     0   0  24   0   0
##   *1/*6     0   0   2   0   0
##   *1/*9     0   0   0  10   0
##   *10/*10   0   0  35   0   0
##   *10/*17   0   0   1   0   0
##   *10/*41   0   0   8   0   0
##   *17/*17   0   0   3   0   0
##   *17/*41   0   0   3   0   0
##   *3/*4     3   0   0   0   0
##   *3/*9     0   1   0   0   0
##   *4/*10    0   1   0   0   0
##   *4/*17    0   2   0   0   0
##   *4/*4     2   0   0   0   0
##   *4/*41    0   7   0   0   0
##   *4/*5     3   0   0   0   0
##   *4/*9     0   1   0   0   0
##   *41/*41   0   0   3   0   0
##   *5/*10    0  14   0   0   0
##   *5/*41    0   1   0   0   0
##   *5/*5     1   0   0   0   0
##   *5/*9     0   1   0   0   0
##   *9/*41    0   0   1   0   0
## CYP2D6 allele frequencies:
## 
##   *1  *10  *17   *3   *4  *41   *5   *6   *9 
## 72.1 10.5  3.2  0.5  5.8  3.7  3.1  0.1  1.0
##       
##          0 0.5   1 1.5   2
##   0      6   0   0   0   0
##   0.25   0  15   0   0   0
##   0.5    3  12  35   0   0
##   0.75   0   0   9   0   0
##   1      0   1  96   0   0
##   1.25   0   0   0  56   0
##   1.5    0   0   5  71   0
##   2      0   0   0   0 407
##                Activity Score
## CYP2D6 Genotype   0 0.25 0.5 0.75   1 1.25 1.5   2
##         *1/*1     0    0   0    0   0    0   0 407
##         *1/*10    0    0   0    0   0   56   0   0
##         *1/*17    0    0   0    0   0    0  34   0
##         *1/*3     0    0   0    0   0    0   3   0
##         *1/*4     0    0   0    0  62    0   0   0
##         *1/*41    0    0   0    0   0    0  27   0
##         *1/*5     0    0   0    0  24    0   0   0
##         *1/*6     0    0   0    0   0    0   2   0
##         *1/*9     0    0   0    0   0    0  10   0
##         *10/*10   0    0  35    0   0    0   0   0
##         *10/*17   0    0   0    1   0    0   0   0
##         *10/*41   0    0   0    8   0    0   0   0
##         *17/*17   0    0   0    0   3    0   0   0
##         *17/*41   0    0   0    0   3    0   0   0
##         *3/*4     0    0   3    0   0    0   0   0
##         *3/*9     0    0   0    0   1    0   0   0
##         *4/*10    0    1   0    0   0    0   0   0
##         *4/*17    0    0   2    0   0    0   0   0
##         *4/*4     2    0   0    0   0    0   0   0
##         *4/*41    0    0   7    0   0    0   0   0
##         *4/*5     3    0   0    0   0    0   0   0
##         *4/*9     0    0   1    0   0    0   0   0
##         *41/*41   0    0   0    0   3    0   0   0
##         *5/*10    0   14   0    0   0    0   0   0
##         *5/*41    0    0   1    0   0    0   0   0
##         *5/*5     1    0   0    0   0    0   0   0
##         *5/*9     0    0   1    0   0    0   0   0
##         *9/*41    0    0   0    0   1    0   0   0

Basic data plots

weight

##       country outcome_primary.1 outcome_primary.2
## 1      Brazil                26               156
## 2    Cambodia                50                18
## 3    Colombia                36                11
## 4    Ethiopia                16                25
## 5       India                 0                 9
## 6        Peru                20               162
## 7 Philippines                 0                 3
## 8    Thailand                11                56
## 9     Vietnam                 7                29
##       country outcome_primary.1 outcome_primary.2
## 1      Brazil                35               310
## 2    Cambodia                53                36
## 3    Colombia                25                16
## 4    Ethiopia                25                52
## 5       India                 4                54
## 6        Peru                30               384
## 7 Philippines                17                 6
## 8    Thailand                19               171
## 9     Vietnam                 9                44

Methb data

## There are a total of 9632 mthb measurements in 818 patients
## Between day 0 and day 20 there are 5816 measurements. Median (range) per patient is 7 (1 to 12)

## 
## Call:
## lm(formula = log10(day7_mthb) ~ tqmgkgtot, data = pk_summaries)
## 
## Residuals:
##      Min       1Q   Median       3Q      Max 
## -1.11911 -0.16721  0.00514  0.18448  0.62429 
## 
## Coefficients:
##              Estimate Std. Error t value Pr(>|t|)    
## (Intercept) -0.100671   0.024584  -4.095 4.76e-05 ***
## tqmgkgtot    0.065552   0.004891  13.404  < 2e-16 ***
## ---
## Signif. codes:  0 '***' 0.001 '**' 0.01 '*' 0.05 '.' 0.1 ' ' 1
## 
## Residual standard error: 0.2632 on 648 degrees of freedom
##   (72 observations deleted due to missingness)
## Multiple R-squared:  0.2171, Adjusted R-squared:  0.2159 
## F-statistic: 179.7 on 1 and 648 DF,  p-value: < 2.2e-16

## [1] 17.86515
## 
## Call:
## lm(formula = t_12_terminal_rescaled ~ AS_score <= 0.5, data = outcome_dat)
## 
## Residuals:
##    Min     1Q Median     3Q    Max 
## -9.754 -1.990 -0.422  1.425 33.434 
## 
## Coefficients:
##                     Estimate Std. Error t value Pr(>|t|)    
## (Intercept)         18.42601    0.20665  89.166   <2e-16 ***
## AS_score <= 0.5TRUE -0.05197    0.69070  -0.075     0.94    
## ---
## Signif. codes:  0 '***' 0.001 '**' 0.01 '*' 0.05 '.' 0.1 ' ' 1
## 
## Residual standard error: 3.899 on 389 degrees of freedom
##   (709 observations deleted due to missingness)
## Multiple R-squared:  1.455e-05,  Adjusted R-squared:  -0.002556 
## F-statistic: 0.005662 on 1 and 389 DF,  p-value: 0.9401

Weight based models of tafenoquine efficacy

## Using all data (n=1073), the odds ratio for recurrence at 4 months for each additional mg/kg of tafenoquine is 0.7 (95% CI 0.65 to 0.75)
## Using all data (n=1073), the odds ratio for recurrence at 4 months for each additional mg/kg of primaquine is 0.63 (95% CI 0.55 to 0.71)
## Using only patients who got a 300 mg dose (n=469), the odds ratio for recurrence at 4 months for each additional mg/kg of tafenoquine is 0.66 (95% CI 0.51 to 0.85)
## Using all patients (n=1073), the odds ratio for recurrence at 6 months for each additional mg/kg of tafenoquine is 0.72 (95% CI 0.67 to 0.77)
## Using all patients (n=1073), the odds ratio for recurrence at 6 months for each additional mg/kg of primaquine is 0.61 (95% CI 0.54 to 0.69)

EMAX model

load fits

Compare the model fits

Figure 2 in paper: the main mg/kg driving efficacy plot under the EMAX model

## The model estimates that a 15 mg/kg TQ dose reduces 95.75% of all recurrences at 4 months

##      2.5%       50%     97.5% 
## 0.5595476 0.6368132 0.7252007

dose-response

##  2.5%   50% 97.5% 
##  10.1  15.4  22.3
##  2.5%   50% 97.5% 
##   4.4   8.0  13.7
##  2.5%   50% 97.5% 
##   1.9   4.7  10.0

Compare for different parts of the world

## 
##       Africa     Americas Asia-Pacific 
##           55          724          321
## In Americas the odds ratio for recurrence for each additional mg/kg increase in tafenoquine dose is 0.81
## In Asia-Pacific the odds ratio for recurrence for each additional mg/kg increase in tafenoquine dose is 0.82
## In Africa the odds ratio for recurrence for each additional mg/kg increase in tafenoquine dose is 0.81

Compare all ORs for logistic regression models

AUC

## Using all data (n=634), the odds ratio for recurrence at 6 months for each additional mg/kg of tafenoquine is 0.6 (95% CI 0.47 to 0.77)
## Using patients who got 300 mg (n=469), the odds ratio for recurrence at 6 months for each additional mg/kg of tafenoquine is 0.91 (95% CI 0.7 to 1.13)

CMAX

## Using all data (n=634), the odds ratio for recurrence at 6 months for each 10 fold increase in tafenoquine CMAX is 0.15 (95% CI 0.06 to 0.31)
## Using who got 300 mg (n=469), the odds ratio for recurrence at 6 months for each 10 fold increase in tafenoquine CMAX is 0.07 (95% CI 0.01 to 0.44)

Terminal elimination half-life and efficacy

## 
## Call:
## lm(formula = t_12_terminal_rescaled ~ log(weight) + country, 
##     data = outcome_dat)
## 
## Residuals:
##    Min     1Q Median     3Q    Max 
## -9.532 -1.975 -0.385  1.432 33.993 
## 
## Coefficients:
##                    Estimate Std. Error t value Pr(>|t|)   
## (Intercept)         9.02208    3.60674   2.501  0.01262 * 
## log(weight)         2.11378    0.83738   2.524  0.01183 * 
## countryCambodia     0.19427    0.93459   0.208  0.83540   
## countryColombia     0.50455    1.07202   0.471  0.63805   
## countryEthiopia    -0.47763    0.80133  -0.596  0.55135   
## countryIndia        0.04244    0.66988   0.063  0.94951   
## countryPeru         1.16167    0.40278   2.884  0.00406 **
## countryPhilippines  1.88886    2.17048   0.870  0.38449   
## countryThailand     0.02899    0.51722   0.056  0.95533   
## countryVietnam      0.30310    0.78000   0.389  0.69771   
## ---
## Signif. codes:  0 '***' 0.001 '**' 0.01 '*' 0.05 '.' 0.1 ' ' 1
## 
## Residual standard error: 3.715 on 639 degrees of freedom
##   (451 observations deleted due to missingness)
## Multiple R-squared:  0.03419,    Adjusted R-squared:  0.02059 
## F-statistic: 2.514 on 9 and 639 DF,  p-value: 0.007827

## 
##  Pearson's product-moment correlation
## 
## data:  outcome_dat$weight and outcome_dat$t_12_terminal_rescaled
## t = 3.1948, df = 642, p-value = 0.001468
## alternative hypothesis: true correlation is not equal to 0
## 95 percent confidence interval:
##  0.04830372 0.20041913
## sample estimates:
##       cor 
## 0.1250965
## Using all data (n=629), the odds ratio for recurrence at 6 months for each additional day in the tafenoquine half life is 1.15 (95% CI 1.07 to 1.23)
## Using all data (n=465), the odds ratio for recurrence at 6 months for each additional day in the tafenoquine half life is 1.17 (95% CI 1.08 to 1.27)

Methaemoglobin

## 
## Family: binomial 
## Link function: logit 
## 
## Formula:
## outcome_primary ~ s(day7_mthb, k = 3) + tqmgkgtot + s(studysite, 
##     bs = "re")
## 
## Parametric coefficients:
##             Estimate Std. Error z value Pr(>|z|)    
## (Intercept) -0.27559    0.43874  -0.628  0.52992    
## tqmgkgtot   -0.28357    0.07931  -3.575  0.00035 ***
## ---
## Signif. codes:  0 '***' 0.001 '**' 0.01 '*' 0.05 '.' 0.1 ' ' 1
## 
## Approximate significance of smooth terms:
##                 edf Ref.df Chi.sq p-value   
## s(day7_mthb)  1.039  1.076  4.168 0.04979 * 
## s(studysite) 12.039 19.000 27.830 0.00204 **
## ---
## Signif. codes:  0 '***' 0.001 '**' 0.01 '*' 0.05 '.' 0.1 ' ' 1
## 
## R-sq.(adj) =  0.0975   Deviance explained = 12.4%
## UBRE = -0.005556  Scale est. = 1         n = 569
## Generalized linear mixed model fit by maximum likelihood (Laplace
##   Approximation) [glmerMod]
##  Family: binomial  ( logit )
## Formula: outcome_primary ~ log(day7_mthb) * tqmgkgtot - day7_mthb + (1 |  
##     studysite)
##    Data: outcome_dat
## 
##      AIC      BIC   logLik deviance df.resid 
##    773.6    796.5   -381.8    763.6      719 
## 
## Scaled residuals: 
##     Min      1Q  Median      3Q     Max 
## -2.3155 -0.6075 -0.3745  0.8231  4.1582 
## 
## Random effects:
##  Groups    Name        Variance Std.Dev.
##  studysite (Intercept) 0.9956   0.9978  
## Number of obs: 724, groups:  studysite, 20
## 
## Fixed effects:
##                          Estimate Std. Error z value Pr(>|z|)    
## (Intercept)               0.01167    0.31226   0.037  0.97018    
## log(day7_mthb)            0.37421    0.23059   1.623  0.10463    
## tqmgkgtot                -0.31206    0.05551  -5.621  1.9e-08 ***
## log(day7_mthb):tqmgkgtot -0.16305    0.05924  -2.752  0.00592 ** 
## ---
## Signif. codes:  0 '***' 0.001 '**' 0.01 '*' 0.05 '.' 0.1 ' ' 1
## 
## Correlation of Fixed Effects:
##             (Intr) lg(7_) tqmgkg
## lg(dy7_mth)  0.183              
## tqmgkgtot   -0.437 -0.391       
## lg(dy7_mt): -0.060 -0.744 -0.025
## Using all data (n=569), the odds ratio for recurrence at 6 months for each absolute percentage increase in methaemoglobin is 0.82 (95% CI 0.67 to 0.98)

Everything

## Generalized linear mixed model fit by maximum likelihood (Laplace
##   Approximation) [glmerMod]
##  Family: binomial  ( logit )
## Formula: outcome_primary ~ tqmgkgtot * log10(day7_mthb) - log10(day7_mthb) +  
##     scale(CMAX) + scale(AUC) + scale(t_12_terminal_rescaled) +  
##     scale(logpara0) + (1 | studysite)
##    Data: outcome_dat
## 
##      AIC      BIC   logLik deviance df.resid 
##    562.7    597.4   -273.4    546.7      558 
## 
## Scaled residuals: 
##     Min      1Q  Median      3Q     Max 
## -1.7545 -0.5372 -0.3803 -0.1230  3.9730 
## 
## Random effects:
##  Groups    Name        Variance Std.Dev.
##  studysite (Intercept) 0.6069   0.779   
## Number of obs: 566, groups:  studysite, 20
## 
## Fixed effects:
##                               Estimate Std. Error z value Pr(>|z|)   
## (Intercept)                   -0.73052    0.55583  -1.314  0.18875   
## tqmgkgtot                     -0.15099    0.11031  -1.369  0.17107   
## scale(CMAX)                    0.49729    0.58113   0.856  0.39215   
## scale(AUC)                    -0.80410    0.49696  -1.618  0.10566   
## scale(t_12_terminal_rescaled)  0.49609    0.16956   2.926  0.00344 **
## scale(logpara0)                0.17300    0.12032   1.438  0.15049   
## tqmgkgtot:log10(day7_mthb)    -0.21143    0.09744  -2.170  0.03001 * 
## ---
## Signif. codes:  0 '***' 0.001 '**' 0.01 '*' 0.05 '.' 0.1 ' ' 1
## 
## Correlation of Fixed Effects:
##             (Intr) tqmgkg s(CMAX s(AUC) s(_12_ scl(0)
## tqmgkgtot   -0.865                                   
## scale(CMAX)  0.432 -0.405                            
## scale(AUC)  -0.153  0.142 -0.911                     
## scl(t_12__)  0.055 -0.083  0.644 -0.730              
## scal(lgpr0) -0.044  0.028 -0.095  0.062  0.031       
## tqmg:10(7_)  0.016 -0.197 -0.295  0.259 -0.056  0.030

Phase 1: relationship with DHA/PQP?

## 
## Call:
## glm(formula = log10(day7_mthb) ~ tqmgkgtot + TYPE, data = pk_summaries)
## 
## Deviance Residuals: 
##     Min       1Q   Median       3Q      Max  
## -1.1253  -0.1679   0.0104   0.1811   0.6181  
## 
## Coefficients:
##              Estimate Std. Error t value Pr(>|t|)    
## (Intercept) -0.151522   0.036502  -4.151 3.75e-05 ***
## tqmgkgtot    0.064592   0.004908  13.161  < 2e-16 ***
## TYPE         0.062112   0.033011   1.882   0.0603 .  
## ---
## Signif. codes:  0 '***' 0.001 '**' 0.01 '*' 0.05 '.' 0.1 ' ' 1
## 
## (Dispersion parameter for gaussian family taken to be 0.06901405)
## 
##     Null deviance: 57.344  on 649  degrees of freedom
## Residual deviance: 44.652  on 647  degrees of freedom
##   (72 observations deleted due to missingness)
## AIC: 111.87
## 
## Number of Fisher Scoring iterations: 2
## 
##      CQ    None      AL DHA/PQP 
##     578      24      24      24

Power calculations and trial design

Power calculations

Superiority of 450 over 300 mg single dose